Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Catecholamine secretions during continuous receptor stimulations by histamine, muscarine and bradykinin in the rat adrenal medulla commonly consisted of two phases, a transient initial secretion followed by a sustained secretion. On activating protein kinase C (PKC) by phorbol dibutyrate (PDBu), both phases of histamine-evoked secretion were inhibited whereas the initial phase alone was inhibited with muscarine. In contrast, bradykinin-evoked secretion as a whole was potentiated. Similar modes of modulations were exhibited when the secretions with these agonists were elicited in muscarine- or bradykinin-pretreated medullae in which PKC had been activated by endogenous processes. It is suggested that PKC may selectively affect the receptors or/and GTP-binding proteins to cause the differential effects on the secretory response in the rat adrenal medulla.
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PMID:Differential effects of protein kinase C activation on catecholamine secretions evoked by stimulations of various receptors in the rat adrenal medulla. 166 May 76

The release of arachidonic acid from cellular phospholipids and its subsequent conversion to eicosanoids is the common early response of skin keratinocytes to a wide variety of exogenous or endogenous agonists including irritant skin mitogens such as the phorbol ester, 4 beta-phorbol 12-myristate 13-acetate (PMA) or the inflammatory peptide bradykinin. In mouse keratinocytes labeled with [14C]arachidonic acid, both PMA and bradykinin induced the release of the fatty acid in a dose-dependent and time-dependent manner. Three lines of evidence indicate phospholipase A2 activity to be involved in arachidonic acid release: (a) its inhibition by mepacrine, (b) the concomitant generation of lysophosphatidylcholine from [3H]choline-labeled cells and (c) an increase in arachidonic acid release from 14C-labeled phosphatidylcholine in particulate fractions from PMA-treated and bradykinin-treated keratinocytes. Inhibition or down regulation of protein kinase C (PKC) led to a suppression of PMA-induced but not bradykinin-induced arachidonic acid release, indicating a critical involvement of this kinase in phorbol-ester-induced activation of epidermal phospholipase A2 activity. Bradykinin-induced activation of phospholipase A2 was however, shown to be mediated by specific B2 receptors coupled to GTP-binding proteins (G protein). In support of this mechanism it was demonstrated that the bradykinin-induced phospholipase A2 activity was increased in the presence of non-hydrolysable GTP but decreased upon addition of non-hydrolysable GDP analogues. Moreover, cholera toxin stimulated both basal and bradykinin-induced phospholipase A2 activity in a cAMP-independent manner, whereas pertussis toxin was found to be inactive in this respect. The data suggest that epidermal phospholipase A2 activity can be stimulated by bradykinin via a B2 receptor-G-protein-dependent pathway, which is independent of PKC and a PKC-dependent pathway which is activated by phorbol esters such as PMA.
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PMID:Activation of a keratinocyte phospholipase A2 by bradykinin and 4 beta-phorbol 12-myristate 13-acetate. Evidence for a receptor-GTP-binding protein versus a protein-kinase-C mediated mechanism. 166 19

The influence of noradrenaline and protein kinase C modulators on (+)-[3H]isradipine binding to voltage-dependent calcium channels has been studied in membranes of equine portal vein smooth muscle and intact strips isolated from rat portal vein. Specific (+)-[3H]isradipine binding to intact strips was increased by noradrenaline, a combination of aluminium and fluoride, and phorbol esters. The increase in isradipine binding induced by noradrenaline was inhibited by 1 microM prazosin while that induced by phorbol esters was inhibited by H7 (a protein kinase C inhibitor). In strips pretreated 6 h with 10 micrograms.ml-1 pertussis toxin, the noradrenaline-induced increase in isradipine binding was unchanged. In contrast, isradipine binding to membranes was unaffected by noradrenaline or GTP-gamma-S. Only phorbol esters had a stimulatory effect on isradipine binding when membranes were incubated in a medium containing 10 microM ATP and 5 mM Mg2+. Scatchard plot analysis reveals that the stimulation of isradipine binding by both noradrenaline and phorbol esters appears to result from a decrease in KD rather than an effect on the maximal binding capacity. Contractions evoked by noradrenaline were concentration-dependently depressed by isradipine. About 30% of the response was resistant to inhibition, while KCl-induced contractions were completely blocked. However, noradrenaline-induced contractions were more sensitive to isradipine inhibition than were KCl-induced contractions. These results suggest that activation of protein kinase C modulates isradipine binding to voltage-dependent Ca2+ channels independently of a separate modulation by membrane depolarization.
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PMID:Modulation of [3H]dihydropyridine binding by activation of protein kinase C in vascular smooth muscle. 166 46

The influence of noradrenaline and protein kinase C modulators on (+)-[3H]isradipine binding to voltage-dependent calcium channels has been studied in membranes of equine portal vein smooth muscle and intact strips isolated from rat portal vein. Specific (+)-[3H]isradipine binding to intact strips was increased by noradrenaline and phorbol esters. The increase in isradipine binding induced by noradrenaline was inhibited by 1 microM prazosin and H7 (a protein kinase C inhibitor), while that induced by phorbol esters was only inhibited by H7. In strips pretreated with 10 micrograms/ml pertussis toxin for 6 h, the noradrenaline-induced increase in isradipine binding was unchanged. In contrast, isradipine binding to membranes was unaffected by noradrenaline or GTP-gamma-S. Only phorbol esters had a stimulatory effect on isradipine binding when membranes were incubated in a medium containing 10 microM ATP and 1 mM Mg2+. Scatchard plot analysis reveals that the stimulation of isradipine binding by both noradrenaline and phorbol esters appears to result from a decrease in KD rather than an effect on the maximal binding capacity. Contractions evoked by noradrenaline were concentration-dependently depressed by isradipine. About 30% of the response was resistant to inhibition, while KCl-induced contractions were completely blocked. However, noradrenaline-induced contractions were more sensitive to isradipine inhibition than were KCl-induced contractions. These results suggest that activation of protein kinase C modulates isradipine binding to voltage-dependent Ca2+ channels.
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PMID:Pharmacology of Ca2+ channels in smooth muscle. 166 62

T cell stimulation via the TCR complex (TCR/CD3 complex) results in activation of the guanine nucleotide binding proteins encoded by the ras protooncogenes (p21ras). In the present study we show that the activation state of p21ras in T lymphocytes can also be controlled by triggering of the CD2 Ag. The activation state of p21ras is controlled by GTP levels on p21ras. In T cells stimulation of protein kinase C is able to induce an accumulation of "active" p21ras-GTP complexes due to an inhibitory effect of protein kinase C stimulation on the intrinsic GTPase activity of p21ras. The regulatory effect of protein kinase C on p21ras GTPase activity appears to be mediated via regulation of GAP, the GTPase activating protein of p21ras. In the present report, we demonstrate that the TCR/CD3 complex and the CD2 Ag control the accumulation of p21ras-GTP complexes via a regulatory effect on p21ras GTPase activity. The TCR/CD3 complex and CD2 Ag are also able to control the cellular activity of GAP. These data demonstrate that p21ras is part of the signal transduction responses controlled by the CD2 Ag, and reveal that the TCR/CD3 complex and CD2 Ag control the activation state of p21ras via a similar mechanism.
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PMID:CD2 antigen mediated activation of the guanine nucleotide binding proteins p21ras in human T lymphocytes. 167 18

Adrenergic, cholinergic, and a variety of peptide neurotransmitters are known to modulate Ca currents in peripheral neurons. Using a protocol that allows for simultaneous assessment of effects on dihydropyridine (DHP)-sensitive and DHP-insensitive current components, we compared the actions of norepinephrine (NE), bethanechol (BeCh), and neuropeptide Y (NPY) on Ca currents in neonatal rat superior cervical ganglion neurons. Here, we show that these transmitters selectively depress the activity of DHP-insensitive Ca channels. Intracellular application of GTP-gamma-S, an activator of GTP-binding proteins, also exclusively affected the DHP-insensitive current, whereas 1,2-oleoylacetylglycerol (OAG), a protein kinase C (PKC) activator, depressed both the DHP-sensitive and DHP-insensitive currents. Pertussis toxin interrupted the coupling between NE and its effector, whereas three different inhibitors of PKC did not. Thus, we confirmed that the selective actions of the transmitters on Ca current appear to be mediated via GTP-binding proteins, but we found no evidence for direct involvement of PKC and conclude that the observed actions of OAG are distinct from those mediated by the neurotransmitters studied.
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PMID:Neurotransmitter modulation of calcium channels in rat sympathetic neurons. 167 23

A large number of neurotransmitters have now been shown to reduce the amplitude and slow the activation kinetics of whole cell HVA ICa in a great diversity of neurons. These transmitters include L-glutamate (AMPA/kainate, metabotropic and NMDA receptors), GABA (via GABAB receptors, NA (via alpha 2 receptors), 5-HT, NA (via alpha 2 receptors), DA and several peptides. Both whole-cell and single-channel studies have demonstrated that the N-channel is the most common channel type to be blocked by transmitters, although an inhibition of the L-type channel has also occasionally been reported. The suppression of the N-type Ca current was commonly shown to be voltage-dependent, with a relief at large positive voltages. Strong evidence has been put forward showing that the transmitter action is mediated by a G-protein, with GDP-beta-S blocking transmitter action, and GTP-gamma-S directly inhibiting the Ca channel. Moreover, pertussis toxin blocked the transmitter action in most neurons, and following such block, injection of the G-protein Go restored transmitter action. A direct link between the G-protein and the Ca channel has been widely theorized to mediate the action of transmitters on certain neurons. There is also some evidence that certain transmitters in specific neurons mediate calcium channel inhibition through a 2nd messenger, perhaps protein kinase C. Transmitters have also been found, although uncommonly, to inhibit HVA L-type and LVA T-type channels. In addition, an enhancement of both HVA and LVA Ca currents by transmitters has been demonstrated, and substantial evidence exists for mediation of this action by cAMP.
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PMID:Modulation of vertebrate neuronal calcium channels by transmitters. 168 17

We have used a digitonin-permeabilized cell system to study the signal transduction pathways responsible for stimulus-secretion coupling in the rat peritoneal mast cell. Conditions were established for permeabilizing the mast cell plasma membrane without disrupting secretory vesicles. Exocytotic release of histamine from digitonin-permeabilized cells required a combination of micromolar concentrations of Ca2+ and the stable guanine nucleotide analogue guanosine 5'-[gamma-thio]triphosphate (GTP[S]), but was independent of exogenous ATP. In the presence of 40 microM-GTP[S], exocytosis was half-maximal at 1.3 microM-Ca2+ and maximal at 10 microM-Ca2+; GTP[S] alone (100 microM) had no effect on histamine release in the absence of added Ca2+. In the presence of 10 microM free Ca2+, 5 microM-GTP[S] was required for half-maximal exocytosis. To examine the possible role of protein kinase C (PKC) in exocytosis, we utilized 12-O-tetradecanoylphorbol 13-acetate (TPA) to activate PKC and studied its effect on histamine release from permeabilized mast cells. Cells that had been incubated with TPA (25 nM for 5 min) exhibited increased sensitivity to both GTP[S] and Ca2+. The PKC inhibitor staurosporine blocked the effect of TPA without inhibiting normal exocytosis in response to the combination of GTP[S] and Ca2+. In addition, down-regulation of mast-cell PKC by long-term TPA treatment (25 nM for 20 h) blocked the ability of the cells to respond to TPA and inhibited exocytosis in response to Ca2+ and GTP[S] by 40-50%. These results suggest that the sensitivity of the exocytotic machinery of the mast cell can be altered by PKC-catalysed phosphorylation events, but that activation of PKC is not required for exocytosis to occur.
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PMID:Calcium- and guanine-nucleotide-dependent exocytosis in permeabilized rat mast cells. Modulation by protein kinase C. 168 46

1. Bull-frog sympathetic neurones in primary culture were voltage clamped in the whole-cell configuration. The pipette solution contained ATP (5 mM). 2. A hyperpolarization-activated sodium-potassium current (H-current: IH) was separated from other membrane currents in a nominally calcium-free solution containing cobalt (2 mM), magnesium (4 mM), barium (2 mM), tetraethylammonium (20 mM), tetrodotoxin (3 microM), apamin (30 nM) and 4-aminopyridine (1 mM). IH was selectively blocked by caesium (10-300 microM). 3. The steady-state activation of IH occurred between -60 and -130 mV. The H-conductance was 4.1-6.6 nS at the half-activation voltage of -90 mV. With the concentrations of potassium and sodium ions in the superfusate at 20 and 70 mM, respectively, the reversal potential of IH was about -20 mV. IH was activated with a time constant of 2.8 s at -90 mV and 22 degrees C. The Q10 between 16 and 26 degrees C was 4.3. 4. A non-hydrolysable ATP analogue in the pipette solution did not support IH activation. Intracellular 'loading' of GTP-gamma-S (30-500 microM) led to a progressive activation of IH. 5. Forskolin (10 microM) increased the maximum conductance of IH by 70%. This was associated with a depolarizing shift in the half-activation voltage (5-10 mV) and in the voltage dependence of the activation/deactivation time constant of IH. 6. Essentially the same results as with forskolin were obtained by intracellular 'loading' with cyclic AMP (3-10 microM) or bath application of 8-bromo cyclic AMP (0.1-1 mM), dibutyryl cyclic AMP (1 mM) and 3-isobutyl-1-methylxanthine (0.1-1 mM). 7. The protein kinase inhibitor H-8 (1-10 microM) decreased the peak amplitude of IH. Phorbol 12-myristate 13-acetate (10 microM), a protein kinase C activator, was without effect. 8. It is concluded that a voltage-dependent cation current can be regulated by the basal activity of adenylate cyclase, presumably through protein kinase A, in vertebrate sympathetic neurones.
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PMID:Cyclic AMP regulates an inward rectifying sodium-potassium current in dissociated bull-frog sympathetic neurones. 169 Dec 92

Intracellular mediators of exocytosis were investigated using isolated mouse pancreatic acini permeabilized with the bacterial toxin streptolysin O (SLO). Permeabilization was demonstrated by fluorescent staining with ethidium bromide and fluorescein diacetate and release of cytoplasmic lactate dehydrogenase. When SLO-permeabilized acini were incubated at 37 degrees C in Ca2(+)-EGTA buffers containing MgATP, amylase secretion was Ca2+ dependent with an EC50 of 0.40 microM Ca2+ and a maximally effective Ca2+ concentration of 1 microM. Maximal amylase secretion was 330% of that in Ca2(+)-free buffer (basal). The nonhydrolyzable GTP analogue guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S; 30 microM) increased the maximal secretion to 451% of basal in the presence of 1 microM Ca2+ and decreased the EC50 to 0.14 microM Ca2+. Removal of ATP plus addition of antimycin A and 2-deoxy-D-glucose inhibited Ca2(+)-dependent, GTP gamma S-enhanced amylase secretion by 56%. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA; 1 microM) also enhanced maximal secretion to 450% of basal and decreased the EC50 to 0.18 microM Ca2+. Enhancement of amylase secretion by submaximal concentrations of GTP gamma S or TPA was inhibited by the protein kinase C inhibitor staurosporine. These results suggest that Ca2+ stimulation of amylase secretion is potentiated by activation of protein kinase C. However, the enhancement of secretion by GTP gamma S and TPA was additive at their maximally effective concentrations, suggesting that another G protein(s) maybe involved in the terminal steps of exocytosis.
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PMID:Amylase release from streptolysin O-permeabilized pancreatic acini. 169 32


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